This project is a comprehensive, multidisciplinary effort to understand the natural history and modes of transmission of viruses and other infectious agents that are associated with cancer. With numerous intramural and extramural laboratory, clinical, and epidemiologic collaborators, and a core of prospective cohort and case-control studies, the effort is focused on human immunodeficiency virus (HIV), human T-lymphotropic virus types I and II (HTLV-I/-II), hepatitis C virus (HCV), and Kaposi sarcoma-associated herpesvirus (KSHV, also called human herpesvirus 8 or HHV-8). The Second Multicenter Hemophilia Cohort Study (MHCS-II) enrolled and completed prospective follow-up of more than 2500 HCV-exposed persons with hemophilia. A public website was established (https:mhcs-ii.rti.org) with background information and data analysis procedures. Progression of HIV/AIDS was shown to be associated with variants in several immunity-related genes (HLA/KIR, cyclophilin A, RANTES, CX3CR1), and likelihood of hepatitis B virus (HBV) clearance was associated with variants in IL10 and IL20. Among HIV-uninfected participants, spontaneous clearance of HCV was found to be associated with infection at a very young age and in relatively recent calendar years. In collaboration, AIDS progression rate was related to differences in several genes related to immunity. The hepatitis C virus (HCV) epidemic in the U.S. hemophilia population was reconstructed, revealing that most infections occurred prior to use of clotting factor concentrates. Spontaneous clearance of HCV infection was shown to be greatly increased with hepatitis B virus (HBV) co-infection. In addition, among hemophiliacs without HIV, HCV clearance also was clustered in families and increased with early age at infection. An HBV viral load assay was developed, and clearance of HBV was related to variants in the IL-18 gene. Progression of HIV/AIDS was shown to be associated with variants in several immunity-related genes (CUL5, cyclophilin A, TSG101, and HLA/KIR), and new methods were developed to analyze these complex relationships. A four-year case-control study of classical (non-AIDS) Kaposi sarcoma and KSHV infection throughout the island of Sicily (where cKS and KSHV are endemic) was completed. Classic KS risk was significantly reduced with current smoking, and it was significantly and independently increased with diabetes and use of corticosteroids. KS transdermal nicotine trial " A 15-week randomized clinical trial was completed, showing that use of transdermal patches to directly deliver nicotine to classic KS lesions was neither harmful nor beneficial. Among HTLV-I-infected people in Jamaica, common variants in HLA Class I genes were associated with a significantly increased risk of adult T-cell leukemia/lymphoma (ATL) and with non-significantly increased levels of HTLV-I proviral load. Common HLA variants were not related to HTLV-associated myelopathy. In a study comparing HTLV-1 carriers with HTLV-1 negative subjects, markers of HTLV-1 infection (infection status, antibody titer, and provirus load) were associated with hematologic and biochemical alterations, such as lymphocyte abnormalities, anemia, decreased eosinophils, and elevated lactate dehydrogenase levels. Using the the U.S. HIV/AIDS Cancer Match Study, study of human immunodeficiency virus (HIV)-infected persons with modest immunosuppression, before the onset of acquired immunodeficiency syndrome (AIDS), demonstrated elevated risk for Kaposi sarcoma (KS, SIR 1,300), non-Hodgkin lymphoma (NHL, 7.3), cervical cancer (2.9) and several non-AIDS-defining malignancies, including Hodgkin lymphoma (5.6 ) and cancers of the lung (2.6 ) and liver (2.7). Non-AIDS-defining cancers comprised 31.4% of cancers in 1991-1995, versus 58.0% in 1996-2002. In a study of cancer risk in the 4-27 month period following AIDS diagnosis, KS incidence was lower in 1996-2002 (335/ 100,000 person-years) than in 1990-1995 (1839/100,000 person-years), NHL incidence pattern was similar (i.e., 390/100,000 person-years in 1996-2002 and 1066/100,000 person-years in 1990-1995). In 1996-2002, for each decline in CD4 cell count of 50 cells per microliter of blood, KS risk increased by 40%, central nervous system non-Hodgkin lymphoma subtypes by 85%, diffuse large B-cell lymphoma 12%, but n increases were demonstrable for Burkitt lymphoma . Kaposi sarcoma (RR = 0.22, 95% CI = 0.20 to 0.24) and for non-Hodgkin lymphoma (RR = 0.40, 95% CI = 0.36 to 0.44) risks were lower in the period of 1996-2002 than in 1990-1995. In persons with HIV/AIDS (PWHAs), the risk of Hodgkin lymphoma (HL) 4 through 27 months after AIDS onset was significantly higher in 1996 to 2002 than earlier. The incidence in PWAs with 150 to 199 CD4 cells/muL was 53.7 per 10(5) py's, whereas in PWAs with fewer than 50 CD4 cells/muL, it was 20.7 per 10(5) py's (P(trend) = .002). For each HL subtype, incidence decreased with declining CD4 counts, but nodular sclerosing decreased more precipitously than mixed cellularity, thereby increasing the proportion of mixed cellularity HL seen in PWAs. The extent standardized incidence ratio (SIR) may underestimate relative risk (RR) of cancer risk among people with HIV/AIDS (PWHA) in registry-based was investigated using the 3 AIDS-related cancers: KS, central nervous system non-Hodgkin lymphoma (CNS NHL) and cervical cancer. SIRs substantially underestimate RRs for KS and CNS NHL, likely from the exceptionally high relative risk of KS and CNS NHL among PWHA. The risk for squamous cell carcinoma of the conjunctiva (SCCC) was observed to be increased in persons with AIDS (SIR, 12.5; 95% CI 7.0 - 20.6) using data from the US HIV/AIDS cancer match study. The relative proportion of was higher among Hispanics and among individuals residing in regions with high ambient ultra violet (u.v.) radiation supporting a role for immunosuppression in SCCC genesis. Risk was unrelated to gender, HIV exposure category, CD4 lymphocyte count, and time relative to AIDS-onset. For HIV/AIDS lymphomas, an analysis of 179 incident lymphomas and matched controls among HIV-1-seropositive homosexual men in the Multicenter AIDS Cohort Study (MACS). Subjects were genotyped for single nucleotide polymorphisms (SNPs) in B-cell stimulatory (IL10, IL10RA, CXCL12, CCL5), allergy-related (IL13, IL4, IL4R) and inflammation-related (BCL6) genes. Compared to the "high IL10" genotype -592CC, carriers of the IL10-592A allele were at lower risk of NHL, and the putative "low-producer IL10" haplotype, -1082A/-819T/-592A was less frequent in cases than controls (16% vs 22%, P=0.03). None of other studied genes differed significantly between cases and controls. Using samples from the KS clonality and gene expression study, we tested the hypothesis that whole KS cells can be transmitted sexually was examined in 25 women by looking for presence of Y-chromosome in KS tumor cells as compared to normal cells. None were positive. Data on human herpesvirus 8 load in peripheral blood has been analyzed and shown to be associated with KS progression and, to a lesser extent, with KS burden. Other correlates include low hemoglobin and low platelets. Collaborations with private and academic laboratories were established to foster development of detection methods for known or possible cancer-associated viruses.